The present invention relates to a process for the preparation of non-steroidal glucocorticoid receptor modulators.
Nuclear receptors are classically defined as a family of ligand dependent transcription factors, that are activated in response to ligand binding (R. M. Evans, 240 Science, 889 (1988)). Members of this family include the following receptors: glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally occurring ligands to these receptors are low molecular weight molecules that play an important role in health and in many diseases. Excesses or deficiencies of these ligands can have profound physiological consequences. As an example, glucocorticoid excess results in Cushing""s Syndrome, while glucocorticoid insufficiency results in Addison""s Disease.
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFxcexa-B. Such interactions result in inhibition of API- and NFxcexa-B-mediated transcription and are believed to be responsible for some of the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
The present invention relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with an amide of the formula 
in the presence of 1,1xe2x80x2-carbonyldiimazole.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with aqueous sodium hydroxide in a polar protic solvent.
The present invention further relates to a process for preparing a compound of the formula 
comprising reducing a compound of the formula 
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with trifluoromethylpropyne.
The present invention further relates to a process for preparing a compound of the formula 
comprising reducing a compound of the formula 
with hydrogen in the presence of a catalyst and potassium carbonate.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with a cyanide source in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with sodium methoxy.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with methyl vinyl ketone.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with pyrrolidine followed by reacting the resultant pyrrolidine enamine intermediate with a benzyl halide.
The present invention relates to a process for preparing a compound of the formula 
comprising (a) reacting a compound of the formula 
with pyrrolidine followed by reacting the resultant pyrrolidine enamine intermediate with a benzyl halide to form the compound of formula IX 
(b) reacting the compound of formula IX so formed with methyl vinyl ketone to form the compound of formula VIII 
(c) reacting the compound of formula VIII so formed with sodium methoxy to form the compound of formula VII 
(d) reacting the compound of formula VII so formed with a cyanide source in the presence of a catalyst to form the compound of formula VI 
(e) reducing the compound of formula VI so formed with hydrogen in the presence of a catalyst and potassium carbonate to form the compound of formula V 
(f) reacting the compound of formula V so formed with trifluoromethylpropyne to form the compound of formula IV 
(g) reducing the compound of formula IV so formed with hydrogen in the presence of a catalyst to form the compound of formula III 
(h) reacting the compound of formula III so formed with aqueous sodium hydroxide in a polar protic solvent to form the compound of formula II 
(i) reacting the compound of formula II so formed with an amide of the formula 
in the presence of 1,1xe2x80x2-carbonyldiimazole.
The present invention relates to a process for prepairing a compound of the formula 
comprising reacting the compound of the formula 
with methyl vinyl ketone.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with a benzyl halide.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with an amine of the formula 
The present invention relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with a borane or a borate.
The present invention relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with a compound of the formula 
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with trimethylsilyl trifluoromethane.
The present invention relates to a process for preparing a compound of the formula 
comprising reacting a compound of the formula 
with an amine of the formula 
in the presence of 1,1xe2x80x2carbonydiimidazole.
The present invention relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with aqueous sodium hydroxide in a polar protic solvent.
The present invention relates to a process for preparing a compound of then formula 
comprising reducing the compound of formula XIII 
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula 
is formed comprising reacting the compound of the formula 
with trifluoromethylpropyne.
The present invention further relates to a process for preparing a compound of the formula 
is formed comprising reducing the compound of formula XV 
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula 
comprising reacting the compound of the formula 
with a cyanide source.
The present invention relates to a compound of the formula 
The present invention relates to a compound of the formula 
The present invention relates to a compound of the formula 
The present invention relates to a compound of the formula 
The present invention relates to a compound of the formula 
The present invention relates to a compound of the formula 

In reaction 1 of Preparation A, the compound of formula X is converted to the corresponding compound of formula XXIII, by reacting X with an amine compound of the formula 
in the presence of a polar aprotic solvent, such as toluene. The reaction is stirred at a temperature between about 90xc2x0 C. to about 150xc2x0 C., preferably about 115xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 2 of Preparation A, the compound of formula XXIII is converted to the corresponding compound of formula XXII, by reacting XXIII with a benzyl halide, such as benzyl bromide, in the presence of a base such as lithium diisopropylamide, and an acid, such as methanesulfonic acid. The reaction is stirred at a temperature between about xe2x88x9278xc2x0 C. to about room temperature, preferably about 25xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 3 of Preparation A, the compound of formula XXII is converted to the corresponding compound of formula VIII, by reacting XXII with methyl vinyl ketone in the presence of an acid, such as sulfuric acid, and a polar aprotic solvent, such as toluene. The reaction is stirred at a temperature between about xe2x88x9240xc2x0 C. to about 180xc2x0 C., preferably about 38xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 1 of Preparation B, the compound of formula VII is converted to the corresponding compound of formula XX, by first treating VII with a base, such as n-butyl lithium, in the presence of a polar solvent, such as tetrahydrofuran. The reaction is stirred a temperature between about xe2x88x92100xc2x0 C. to about xe2x88x9270xc2x0 C., preferably about xe2x88x9278xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours. A borane, such as diphenylborane, or a borate, is then added to the reaction mixture and sodium hydroxide is then added in the presence of hydrogen peroxide. The resulting reaction mixture is stirred at a temperature between about xe2x88x9220xc2x0 C. to about 0xc2x0 C., preferably about xe2x88x9210xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 1 of Preparation C, the compound of formula XIX is converted to the corresponding compound of formula XVIII, by reacting XIX with trimethylsilyl triflouromethane in the presence of tetrabutylammonium fluoride and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at a temperature between about xe2x88x9278xc2x0 C. to about room temperature, preferably about xe2x88x9210xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 2 of Preparation C, the compound of XVIII is converted to the corresponding compound of formula XVII, by reacting XVIII with a compound of the formula 
in the presence of a base. The reaction is stirred at a temperature between about xe2x88x9210xc2x0 C. to about room temperature, preferably about 25xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 1 of Preparation D, the compound of formula XVI is converted to the corresponding compound of formula XV, by reacting XVI with a cyanide source, such as zinc cyanide, in the presence of palladium coupling reagent, such as tetrakis(triphenylphosphine)palladium(0), and a polar protic solvent, such as dimethylformamide. The reaction is stirred at a temperature between about 25xc2x0 C. to about 150xc2x0 C., preferably about 80xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 4 hours.
In reaction 2 of Preparation D, the compound of formula XV is converted to the corresponding compound of formula XIV, by reducing XV with hydrogen, under a pressure between about 20 psi to about 100 psi, preferably about 60 psi, in the presence of a catalyst, such as palladium on carbon, and a polar solvent, such as tetrahydrofuran, followed by treating the reaction mixture with an acid, such as hydrochloric acid. The reaction is stirred at a temperature between about 0xc2x0 C. to about 100xc2x0 C., preferably about 25xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 6 hours.
In reaction 3 of Preparation D, the compound of formula XIV is converted to the corresponding compound of formula XIII, by reacting XIV with trifluoromethylpropyne in the presence of a base, such as potassium tert-butyloxy, and a polar solvent, such as tetrahydrofuran. The reaction is stirred at about xe2x88x9278xc2x0 C. to about xe2x88x9225xc2x0 C., preferably about xe2x88x9210xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 1 hour.
In reaction 4 of Preparation D, the compound of formula XIII is converted to the corresponding compound of formula XII, by reducing XIII with hydrogen, under a pressure between about 10 psi to about 50 psi, preferably about 20 psi, in the presence of a catalyst, such as palladium on carbon. The reaction is stirred at a temperature between about 0xc2x0 C. to about 100xc2x0 C., preferably about 25xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 6 hours.
In reaction 5 of Preparation D, the compound of formula XII is converted to the corresponding compound of formula XI, by reacting XII with 50% aqueous sodium hydroxide in ethanol. The reaction is stirred at a temperature between about 60xc2x0 C. to about 100xc2x0 C., preferably about 80xc2x0 C., for a time period between about 0.5 hours to about 12 hours, preferably about 6 hours.
In reaction 6 of Preparation D, the compound formula XII is converted to the corresponding compound of formula XXVII, by reacting XI with an amine of the formula 
in the presence of 1,1xe2x80x2-carbonyldiimidazole and a polar aprotic solvent, such as tetrahydrofuran. The reaction is heated to reflux for time period between about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 1 of Scheme 1, the compound of formula X is converted to the corresponding compound of formula IX by reacting X with pyrrolidine in the presence of an aprotic solvent, such as toluene. The reaction is heated to a temperature between about 80xc2x0 C. to about 150xc2x0 C., preferably about 115xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The resultant pyrrolidine enamine intermediate is then reacted with benzyl bromide, in an aprotic solvent, such as toluene, at a temperature between about 80xc2x0 C. to about 100xc2x0 C., preferably about 90xc2x0 C., for a time period between about 30 minutes to about 3 hours, preferably about 2 hours.
In reaction 2 of Scheme 1, the compound of formula IX is converted to the compound of formula VII by first heating IX in water and an aprotic solvent, such as toluene, at a temperature between about 25xc2x0 C. to about 110xc2x0 C., preferably about 100xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours. S-(xe2x88x92)-xcex1-methyl benzylamine is then added to the reaction mixture and the solution was heated to a temperature between about 80xc2x0 C. to about 150xc2x0 C., preferably about 115xc2x0 C. The intermediate so formed is then reacted with methyl vinyl ketone. The reaction mixture is then stirred at temperature between about 0xc2x0 C. to about xe2x88x9220xc2x0 C., preferably about xe2x88x9210xc2x0 C., for a time period between about 10 minutes to about 30 minutes, preferably about 20 minutes.
In reaction 3 of Scheme 1, the compound of formula VIII is converted to the corresponding compound of formula VII by first treating VIII with sodium methoxide in the presence of a polar protic solvent, such as ethanol. The reaction mixture is stirred at a temperature between about room temperature to about 80xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The reaction mixture is then added to an acetylchloride ethanol solution and the resulting mixture is allowed to stir at a temperature between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably about 0xc2x0 C., for a time period between about 15 minutes to about 1 hour, preferably about 30 minutes.
In reaction 4 of Scheme 1, the compound of formula VII is converted to the corresponding compound of formula VI by reacting VII with a cyanide source, such as zinc cyanide, in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium(0), and a polar solvent, such as dimethylformamide or dimethylacetamide. The reaction is stirred at a temperature between about 70xc2x0 C. to about 90xc2x0 C., preferably about 80xc2x0 C., for a time period between about 10 hours to about 14 hours, preferably about 12 hours.
In reaction 5 of Scheme 1, the compound of formula VI is converted to the corresponding compound of formula V by reducing VI with hydrogen in the presence of a catalyst, such as palladium on carbon, potassium carbonate and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred under pressure between about 40 psi to about 100 psi, preferably about 60 psi, at room temperature, for a time period about 4 hours to about 6 hours, preferably about 5 hours.
In reaction 6 of Scheme 1, the compound of formula V is converted to the corresponding compound of formula IV by reacting V with trifluoromethylpropyne in the presence of potassium tert-butoxide and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at a temperature between about xe2x88x9220xc2x0 C. to about 0xc2x0 C., preferably about xe2x88x9210xc2x0 C.
In reaction 7 of Scheme 1, the compound of formula IV is converted to the corresponding compound of formula III by reducing IV with hydrogen in the presence of a catalyst, such as palladium on carbon and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred under pressure between about 10 PSI to about 30 PSI, preferably about 20 PSI, at room temperature, for a time period between about 2 hours to about 7 hours, preferably about 5.5 hours.
In reaction 8 of Scheme 1, the compound of formula III is converted to the corresponding compound of formula II by reacting III with aqueous sodium hydroxide in the presence of a polar protic solvent, such as ethanol. The reaction is stirred at a temperature between about 70xc2x0 C. to about 90xc2x0 C., preferably about 80xc2x0 C., for a time period between about 12 hours to about 18 hours, preferably about 15 hours.
In reaction 9 of Scheme 1 the compound of formula II is converted to the corresponding compound of formula I by reacting II with an amine of the formula 
in the presence of 1,1xe2x80x2-carbonyldiimidazole and a polar aprotic solvent, such as tetrahydrofuran. The reaction is heated to reflux for time period between about 1 hour to about 3 hours, preferably about 2 hours.
Experimental Section
All reagents were available from commercial sources and used without purification unless stated otherwise. Melting points were determined on a Thomas Hoover capillary melting point apparatus and were uncorrected. NMR spectra were obtained on an UNITYpIus-400 (400 MHz) spectrometer in deuterochloroform, acetone-d6 or DMSO-d6. Infrared spectra were recorded on a Nicolet Avatar 360 FT-IR. Optical rotations were determined on a Perkin-Elmer 241 polarimeter. Mass spectra were obtained at M-Scan Inc., West Chester, Pa. Elemental analyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y.